Intravenous formulation with water-soluble cocrystals of acetylsalicylic acid and theanine

ABSTRACT

A water-soluble aspirin-theanine cocrystal composition which includes a quantity of acetylsalicylic acid and a quantity of a theanine enantiomer associated with the quantity of acetylsalicylic acid. The composition may be created by a method including the steps of: (i) providing a quantity of acetylsalicylic acid; (ii) adding a quantity of a theanine enantiomer to the quantity of acetylsalicylic acid to form a mixture comprising the quantity of acetylsalicylic acid and the enantiomer of theanine; (iii) wetting the mixture; and (iv) grinding the mixture for a length of time sufficient to produce a dried crystalline mass. The water-soluble cocrystal composition is suitable for intravenous administration, preferably to humans.

FIELD OF THE INVENTION

The present invention relates to a novel method of administeringacetylsalicylic acid, more specifically to a novel intravenousformulation, using a water-soluble cocrystal product of acetylsalicylicacid and theanine that has a neutral pH and provides enhanced stabilityand bioactivity as compared to previously known water-solubleformulations of aspirin.

BACKGROUND OF THE INVENTION

Coronary artery disease is the leading cause of mortality in developedcountries. In the United States, a heart attack occurs approximatelyevery 20 seconds. Aspirin inhibition of cyclooxygenase has been shown tobe beneficial in patients presenting with acute coronary syndrome andacute myocardial infarction. Researchers found that the median plateletinhibition times for chewed baby aspirin 324 mg, soluble aspirin(alka-seltzer) 325 mg, and whole compressed non-enteric coated aspirin324 mg, were 7.5 minutes, 7.5 minutes, and 10.0 minutes, respectively.Schwertner, et al, “Effects of different aspirin formulations onplatelet aggregation times and on plasma salicylate concentration.”Thromb Res. 2006; 118(4): 529-34. Epub 2005 Nov. 18. Within 7.5 minutes,though, an individual could be dead from one of a number of potentiallyfatal arrhythmias such as ventricular tachycardia, ventricularfibrillation or complete heart block. Early administration of a novelintravenous aspirin formulation could start benefitting the patient in amatter of seconds, whereas the full benefit of traditional aspirin maynot take effect until major sequelae, complications or death hasoccurred. In a person presenting with an acute myocardial infarction,intravenous aspirin is the preferred route for early plateletaggregation inhibition. According to the American Heart Association's2007 National STEMI Statistics, 75% of the nation's acute care hospitalsare not capable of performing life-saving PCI (Percutaneous CoronaryIntervention) for STEMI (ST elevation myocardial infarction) patients.As such, there is a clear unmet need for a novel intravenous aspirinwith improved pharmacokinetics and pharmacodynamics in patientspresenting with acute myocardial infarction.

Aspirin inhibits prostanoid biosynthesis, in particular that ofthromboxane A2 and prostaglandins PGE2 and PGI2. Aspirin irreversiblyinhibits platelet cyclooxygenase 1 (COX-1) through acetylation of theamino acid serine at position 529, thereby preventing arachidonic acidaccess to the COX-1 catalytic site through steric hindrance. Byinhibiting COX-1, the platelet is unable to synthesize prostaglandin H2,which would otherwise be converted to thromboxane A2, which causesplatelet aggregation, an early step in the coagulation cascade.

Control of the inflammatory process is regulated by a cascade ofbiomolecular mechanisms. These mechanisms occur via two pathways: thecyclooxygenase pathway, which results in the formation ofprostaglandins, and the lipoxygenase pathway, which results in theformation of leukotrienes. Non-steroid anti-inflammatory drugs (NSAID),like aspirin, function via the cyclooxygenase pathway. There are threemajor human lipoxygenases. They differ in the position of the doublebond on the arachidonic acid molecule. These human lipoxygenases includethe 5-, 12-, and 15-lipoxygenases, which respectively catalyze theinsertion of oxygen at the C-5, C-12 and C-15 positions of arachidonicacid. The resulting leukotrienes and lipoxins provide signalingmolecules associated with avariety of human diseases such as asthma,atherosclerosis, psoriasis and inflammatory bowel disease. Leukotrienesand lipoxins, have been implicated as critical signaling molecules in avariety of cancers. 15-HLO has been shown to be a key biological agentin colorectal cancers, while 12-HLO is involved in pancreatic, breastand prostate cancers. 5-HLO is up-regulated in prostate cancer and itsinhibition abolishes all cell proliferation, inducing apoptosis.

Tylenol accounts for most drug overdoses in the United States and otherWestern countries. The hepatotoxicity of Tylenol (acetaminophen),statins (cholesterol lowering drugs), antiretrovirals (taken for HIV andAIDS), and alcohol are well known. Researchers at Yale University havenow provided new insight into the mechanism by which acetaminophencauses liver damage in mice and determined that aspirin providessubstantial protection from these toxic effects of acetaminophen.Wajahat Z. Mehal; Acetaminophen—induced hepatotoxicity in mice isdependent on Tlr9 and the Nalp3 Inflammasome; Journal of ClinicalInvestigation; Jan. 26, 2009.

Currently, intravenous aspirin is not approved for use in the UnitedStates. The poor solubility of aspirin in water and its rapid hydrolysisin the plasma to salicylic acid and acetic acid have limited itsintravenous use.

Attempts have been made in the past to produce an aspirin product havingan acceptable solubility, but none have proven to be totallysatisfactory.

For example, the introduction of Bayer aspirin, as well as Disprin(distributed in the United Kingdom), into water results in the formationof a cloudy suspension indicative of incomplete dissolution in water.Aspro Clear (distributed in Australia and New Zealand and marketedthroughout Europe) imparts a non-cloudy, snow globe effect in water formore than three minutes after the tablets have effervesced.

It is well-known that lysine acetylsalicylate (sold as, e.g., Aspegicand Aspisol) is suitable for intravenous administration. The suitabilityof lysine for intravenous administration is due to the formation of asalt of acetylsalicylic acid with a basic amino acid, with the salt formexhibiting improved solubility. Lysine acetylsalicylate, however, is notapproved by the FDA for use in the United States. See e.g., FDA Reports2006-2008: Aspegic Side-Effect Report #5076936-8 (after drug wasadministered, patient developed cardio-respiratory arrest andventricular fibrillation and died); FDA Reports 2006-2008: Aspegic SideEffect Report #5379074-X (after drug was administered, patientexperienced angina pectoris and recovered).

U.S. Pat. Nos. 5,665,388 and 5,723,453 to Phykitt, disclose anessentially sodium-free, soluble alkaline aspirin compound. Theformulations disclosed in these references, however, suffer from anumber of disadvantages. One disadvantage is that the use ofbicarbonates, as disclosed therein, causes gas to be formed wheningested by patients. Another disadvantage is that the relatively highpH of the compositions disclosed therein (i.e., greater than 8.0) leadsto rapid hydrolysis and instability of the drug substance and,therefore, a shortened shelf-life.

Many of the formulations disclosed in U.S. Pat. Nos. 5,157,030 and5,776,431 to Galat are formed as two separate compositions (mixture “A”and mixture “B”), which is disadvantageous from manufacturing, packagingand use standpoints. Furthermore, the formulations in these referencesare blended and then directly added to water. There is no indicationthat the blended product is stable. Further, compositions formulated inaccordance with the Galat patents take up to two to three minutes tosubstantially completely dissolve in water.

Compositions formulated in accordance with the methods disclosed inPatent Application Publication No. 2006/0292225 to Felix take up to15-30 seconds to completely dissolve in water with stirring.

Theanine, like aspirin, is known to have salutary effects. It is foundin ordinary tea leaves from Camellia sinensis and the mushroom Xerocomusbadius, but is otherwise rare in nature. Preliminary research, suggeststhat L-theanine promotes alpha wave generation in the brain. Thereby, anawake, alert and relaxed physical and mental condition is achieved,which demonstrates theanine's effectiveness in stress management.L-theanine does not cause drowsiness or impair a person's motor skills.It has been shown to work antagonistically against the negative sideeffects of caffeine, to increase dopamine and serotonin concentrationsin the brain, to be effective in reducing the hypertension anddisturbance of sleep often associated with the use of caffeine, and todiminish symptoms of premenstrual syndrome. Laboratory studies indicatethat theanine produces these effects by increasing the level of GABA(gamma-aminobutyric acid), an important inhibitory neurotransmitter inthe brain.

It has been reported that theanine supports the immune system and mayreduce plasma total cholesterol, cholesterol ester and very-low-densitylipoprotein cholesterol.

Studies on the effects of theanine on alcohol metabolism and hepatictoxicity have shown that theanine is effective against alcoholic liverinjury.

Theanine also has the potential to protect neurons from excesses ofglutamate. Glutamate is an essential brain chemical that may be releasedin excess amounts with some disease conditions (e.g., amyotrophiclateral sclerosis and cerebrovascular dementia) and with brain injuries,as occurs with strokes or physical injuries. Theanine may protectagainst this damage by blocking glutamine entrance to cells due to thesimilarity in the stereochemical structures of theanine and glutamine.

A direct metabolite of amino acids glutamine and glutamic acid, theanineis made different by its ethyl-N alkylation of glutamine's nitrogen. Theamino acid scaffolds glutamine and its metabolite glutamic acid providethe general, alpha amino acid core structure responsible for theanine'stransport, while ethyl-N alkylation of glutamine provides both itstransport and pharmacological properties. The similarity of glutamine'sand glutamic acid's structure with theanine allows theanine to besubstrate and product competitors for all physiological glutamine andglutamic acid reactions, providing their charges are similar. Therefore,wherever glutamine or glutamic acid is a metabolite, theanine canactivate, inhibit or add to target activity. This is why its effects areso far-reaching. It is a glutamine mimetic with pharmacologicalactivity. Glutamine is a significant consumer of ATP for nitrogenincorporation, which may explain some of the anti-cancer and anti-HIVactivity of theanine. If N-fixation is inhibited, cell or viralstructure growth is also inhibited.

The amino acids glutamine and glutamic acid have common molecularelements with theanine. Some examples of common molecular elements arepl(isoelectric point), polarity, hydropathy index, and elements thatsupport their role as metabolite targets for theanine. The overlappingmolecular properties allow theanine to function as a glutamine orglutamic acid analogue. These properties relate to the electrostaticprofile of theanine under physiological conditions and its overallstructural geometry, which includes atoms common to the related coreamino acids glutamine and glutamic acid. The coincident array of atomsand the relative electrostatic structure of glutamine and glutamic acidallow them to serve as targets for theanine. The targets also includethe enzymes, proteins, receptors or other macromolecules theyeffectively bind. In the case of glutamic acid, the atoms that make upthe isosteric structure up to the C5 or gamma carboxyl are in the samearray as theanine. In the case of glutamine, the isosteric andisoelectronic atoms of glutamine are equal to theanine's where hydrogenhas been replaced by ethyl (—C₂H₅) on the carboxamide nitrogen ofglutamine.

Glutathione is the liver's first-line defense against drugs andchemicals. It is used by cancer cells against drugs and chemicals.Cancer cells use glutathione to detoxify doxorubicin and escort the drugout of cells. Theanine is able to interfere with this process due to itsstructural similarity to glutamate. Glutamic acid, or glutamate, is oneof the components of glutathione, the drug detoxifier. Because it lookslike glutamic acid, cancer cells take up and mistakenly use the theanineto create glutathione. But the glutathione they create with theaninedoes not detoxify like natural glutathione. Instead, this theanine-basedglutathione appears to block the ability of cancer cells to detoxify.

Further, in addition to enhancing doxorubicin's cancer-killing effectswithout harming healthy tissue, theanine also keeps doxorubicin out ofhealthy tissue. This is a major added benefit, since one of thedrawbacks of the use of doxorubicin is its toxicity to the heart. Thepotential of theanine as an adjunct to cancer chemotherapy was proposedby researcher Yasuyuki Sadzuka, who confirmed that theanine, a majoramino acid in green tea, enhances the antitumor activity of doxorubicin(DOX) without an increase in DOX-induced side effects. He postulatedthat the action of theanine is due to decreases in glutamate uptake viainhibition of the glutamate transporter and reduction of glutathione andDOX export from the cell. Theanine enhances the antitumor activity notonly of DOX but also of cisplatin and irinotecan (CPT-11). In essence,Sadzuka found that theanine could block the export of doxorubicin(Adriamycin) from cancer cells by blocking the glutamate and glutathionetransporter mechanisms; the elevated level of the drug within cancercells strongly inhibits the tumor. Sadzuka Y, et al., “The effects oftheanine, as a novel biochemical modulator, on the antitumor activity ofadriamycin,” Cancer Letters 1996; 105(2): 203-209; Sadzuka Y, et al.,“Modulation of cancer chemotherapy by green tea,” Clinical CancerResearch 1998; 4(1): 153-156; Sadzuka Y, et al., “Efficacies of teacomponents on doxorubicin induced antitumor activity and reversal ofmultidrug resistance,” Toxicology Letters 2000; 114 (1-3): 155-162;Sadzuka Y, et al., “Improvement of idarubicin induced antitumor activityand bone marrow suppression by theanine, a component of tea,” CancerLetters 2000;158(2): 119-24; Sadzuka Y, et al., “Enhancement of theactivity of doxorubicin by inhibition of glutamate transporter,”Toxicology Letters 2001; 123(2-3):159-67; Sadzuka Y, et al., “Effect ofdihydrokainate on the antitumor activity of doxorubicin,” Cancer Letters2002; 179(2): 157-163.

Therapeutic compounds, such as aspirin, are most stable in a crystallineform, but can display poor aqueous solubilities and slow dissolutionrates. These properties impart the tendency to reduce thebioavailability of the active pharmaceutical ingredient (API), therebyslowing absorption.

A cocrystal is a multiple-component crystal, in which two or moremolecules associate (but do not bond) on the molecular level in solidcrystalline form under ambient conditions. They are attractive to thepharmaceutical industry because they offer opportunities to modify thechemical and/or physical properties of an API without the need to makeor break covalent bonds. In pharmaceutical cocrystals, the molecularstructure of the API is not changed. This has important implications forstreamlined regulatory approval of new forms. By their very nature,APIs, molecules that contain exterior hydrogen-bonding moieties, arepredisposed to formation of cocrystals. Pharmaceutical cocrystals willafford forms of APIs with improved physical properties such assolubility, stability, hygroscopicity, and dissolution rate. Physicalproperties are not just dependent upon molecular structure. They arealso critically dependent upon supramolecular chemistry and itsinfluence upon crystal structure. The application of the concepts ofsupramolecular synthesis and crystal engineering to the development ofpharmaceutical cocrystals offers many opportunities related to drugdevelopment and delivery.

Thus, a water-soluble aspirin-theanine cocrystal composition which hasenhanced stability and bioactivity as compared to previously-known,water-soluble analgesic compositions, and which delivers the salutaryeffects of both aspirin and theanine, is needed.

The present invention satisfies these and other medical needs andovercomes deficiencies found in the prior art.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide awater-soluble aspirin-theanine cocrystal composition having acrystalline structure and which has enhanced stability and bioactivity,as compared to previously-known, water-soluble analgesic compositions.

A further object of the present invention is to provide a water-solubleaspirin-theanine cocrystal composition having the above characteristicsand which is rapidly water-soluble.

Yet a further object of the present invention is to provide awater-soluble aspirin-theanine cocrystal composition having the abovecharacteristics and which may be used in the relatively large dosagesthat are required for anti-inflammatory treatment.

It is an object of the present invention to provide a method ofadministering a water-soluble aspirin-theanine cocrystal compositionintravenously in humans that has a neutral pH, provides enhancedstability and bioactivity, and is suitable for treatment of variousdiseases and medical conditions.

Still another object of the present invention is to provide aqueousaspirin-theanine cocrystal formulations suitable for intravenousadministration having the above characteristics and which allow forrapid delivery of acetylsalicylic acid to the bloodstream.

Yet a further object of the present invention is to provide aqueousaspirin-theanine cocrystal formulations suitable for intravenousadministration having the above characteristics and which may be usedfor extended periods of time without causing the gastrointestinal upsetand/or erosions, bleeding, or perforation of the gastrointestinal tractwhich may occur with conventional oral aspirin.

Another object of the present invention is to provide aqueousaspirin-theanine cocrystal formulations suitable for intravenousadministration having the above characteristics and which allow fordelivery of therapeutic quantities of theanine to the bloodstream.

These and other objects of the present invention are achieved inaccordance with one embodiment of the present invention by provision ofa water-soluble aspirin-theanine cocrystal composition which includes aquantity of acetylsalicylic acid and a quantity of a theanine enantiomerassociated with the quantity of acetylsalicylic acid, the cocrystalcomposition being formed by physically combining the quantity ofacetylsalicylic acid and the quantity of a theanine enantiomer into amixture and wetting the mixture with a quantity of a wetting agent andgrinding the combination for a length of time sufficient to produce adried-crystalline mass. In some embodiments, the wetting agent employedis methanol.

Formulations according to embodiments of the present invention protectaspirin from hydrolysis, with the bulk active ingredient being awell-defined, free-flowing crystalline solid which has enhancedstability and bioactivity. The solid has a solubility in water of about10 mg/mL, and yields a clear aspirin solution shortly after being mixed.

Compositions according to embodiments of the present invention are verysoluble in water, requiring about less than one part water per partsolute, especially when compared to traditional aspirin, which is onlyvery slightly soluble, requiring about 1,000 to 10,000 parts water perpart solute.

In accordance with an embodiment of the present invention, a method ofcreating a water-soluble aspirin-theanine cocrystal composition includesthe steps of (i) providing a quantity of acetylsalicylic acid; adding aquantity of a theanine enantiomer to the quantity of acetylsalicylicacid to form a mixture comprising the quantity of acetylsalicylic acidand the enantiomer of theanine; (ii) wetting the mixture; and (iii)grinding the mixture for a length of time sufficient to produce a driedcrystalline mass. In certain of these embodiments, methanol is employedin the step of wetting the mixture. In certain of these embodiments, thedried crystalline mass has an aqueous solubility of at least about 9.0mg/mL.

In some embodiments of the present invention the quantity ofacetylsalicylic acid falls within the range of about 5% to 95% by weightof the mixture of the quantity of acetylsalicylic acid and the quantityof a theanine enantiomer. In other embodiments, the quantity ofacetylsalicylic acid falls within the range of about 15% to 85% byweight of the mixture of the quantity of acetylsalicylic acid and thequantity of a theanine enantiomer. In further embodiments, the quantityof acetylsalicylic acid is about 50% by weight of the mixture of thequantity of acetylsalicylic acid and the quantity of a theanineenantiomer.

In some of these embodiments, the theanine enantiomer is the L-form. Inother embodiments, the theanine enantiomer is the D-form. In furtherembodiments, the theanine enantiomer is the DL-form.

In some of these embodiments, the resultant aspirin-theanine cocrystalcomposition is dissolved in a solvent to form an aspirin-theaninecocrystal solution. In certain of these embodiments, the solvent iswater. In certain of these embodiments, the resultant aspirin-theaninecocrystal solution has a pH that is physiologic. In certain of theseembodiments, the resultant aspirin-theanine cocrystal solution has a pHin the range of about 7.35 to about 7.45. In certain of theseembodiments, the resultant aspirin-theanine cocrystal solution has a pHwhich is about 7.4.

In accordance with another embodiment of the present invention, a methodof creating a water-soluble aspirin-theanine cocrystal compositionincludes the steps of: (i) providing a quantity of acetylsalicylic acid;(ii) adding a quantity of an enantiomer of theanine to said quantity ofacetylsalicylic acid to form a mixture comprising said quantity ofacetylsalicylic acid and said enantiomer of theanine; (iii) dissolvingsaid combination in a quantity of a solvent to form a solution; and (iv)drying said solution for a length of time sufficient to produce a driedcrystalline mass. In certain of these embodiments, the dried crystallinemass has an aqueous solubility of at least about 9.4 mg/mL. In certainof these embodiments, water is employed as the solvent. In certain ofthese embodiments, the drying step is performed by means of a rotaryevaporation process.

In certain of these embodiments, the theanine enantiomer is the L-form.In some of these embodiments the theanine enantiomer is the D-form. Infurther of these embodiments, the theanine enantiomer is the DL-form.

In some embodiments of the present invention, the theanine enantiomerfurther comprises a carbohydrate functional group thereon. In theseembodiments, the carbohydrate functional group may be of theL-configuration or the D-configuration. In these embodiments, thecarbohydrates employed may be monosaccharides, disaccharides,trisaccharides, oligosaccharides or polysaccharides.

In some embodiments of the present invention, the theanine enantiomerfurther comprises an amino acid functional group thereon. In certain ofthese embodiments, the amino acid functional group is a dipeptide.

The various features of novelty which characterize the invention arepointed out with particularity in the claims annexed to and forming apart of this disclosure. For a better understanding of the invention,its operating advantages and specific objects attained by its uses,reference is made to the accompanying figures and descriptive matter inwhich a preferred embodiment of the invention is illustrated.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 depicts photomicrographs taken at two magnifications of thecrystalline cocrystal product formed by acetylsalicylic acid andL-theanine according to embodiments of the present invention;

FIG. 2 is a differential scanning calorimetry thermogram of thecocrystal formed by acetylsalicylic acid and L-theanine according toembodiments of the present invention;

FIG. 3 is an x-ray powder diffraction pattern of the cocrystal formed byacetylsalicylic acid and L-theanine according to embodiments of thepresent invention;

FIG. 4 is an infrared absorption spectrum of the cocrystal formed byacetylsalicylic acid and L-theanine according to embodiments of thepresent invention;

FIG. 5 is a Raman spectrum of the cocrystal formed by acetylsalicylicacid and L-theanine according to embodiments of the present invention;

FIG. 6 depicts photomicrographs taken at two magnifications of thecrystalline cocrystal product formed by acetylsalicylic acid andD-theanine;

FIG. 7 is a differential scanning calorimetry thermogram of thecocrystal formed by acetylsalicylic acid and D-theanine according toembodiments of the present invention;

FIG. 8 is an x-ray powder diffraction pattern of the cocrystal formed byacetylsalicylic acid and D-theanine according to embodiments of thepresent invention;

FIG. 9 is an infrared absorption spectrum of the cocrystal formed byacetylsalicylic acid and D-theanine according to embodiments of thepresent invention;

FIG. 10 is a Raman spectrum of the cocrystal formed by acetylsalicylicacid and D-theanine according to embodiments of the present invention;

FIG. 11 depicts photomicrographs taken at two magnifications of thecrystalline cocrystal product formed by acetylsalicylic acid andDL-theanine;

FIG. 12 is a differential scanning calorimetry thermogram of thecocrystal formed by acetylsalicylic acid and DL-theanine according toembodiments of the present invention;

FIG. 13 is an x-ray powder diffraction pattern of the cocrystal formedby acetylsalicylic acid and DL-theanine according to embodiments of thepresent invention;

FIG. 14 is an infrared absorption spectrum of the cocrystal formed byacetylsalicylic acid and DL-theanine according to embodiments of thepresent invention; and

FIG. 15 is a Raman spectrum of the cocrystal formed by acetylsalicylicacid and DL-theanine according to embodiments of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention satisfies needs left unresolved by the prior artby providing a method for synthesizing a soluble cocrystal formed byacetylsalicylic acid and L-theanine which is readily administerable toindividuals through a variety of media.

Embodiments of the present invention employ L-theanine, a rare aminoacid. L-theanine is a water-soluble, white crystalline powder, having aChemical Abstracts Service (CAS) Registry Number of 3081-61-6 and a GRASclassification (GRAS Notice Number: GRN 000209). L-theanine has theempirical formula C₇H₁₄N₂O₃, a molecular weight of 174.20, and thesystematic name of 2-Amino-4-(ethylcarbamoyl)butyric acid. Being5-N-ethyl glutamine, theanine differs from glutamine by the CH2-CH3(ethyl) group (replacing hydrogen). N-Ethyl confers on theanine itsactive properties.

Embodiments of the present invention include cocrystals ofacetylsalicylic acid with theanine (5-N-ethyl-glutamine). Further, thetheanine contained in compositions according to embodiments of thepresent invention may be of any of L-form, D-form, DL-form.

Embodiments of the present invention may include the amino acidscaffolds glutamine and/or glutamic acid.

Non-limiting examples of enantiomers utilized in embodiments accordingto the present invention may include a D-enantiomer of Theanine,D-Glu(NHEt)-OH, 2 R enantiomer; an L-enantiomer of Theanine,L-Glu(NHEt)-OH, 2R enantiomer; a DL enantiomer of Theanine,DL-Glu(NHEt)-OH enantiomer; a D-enantiomer of Theanine, D-Gln(Et)-OH, 2Renantiomer; an L-enantiomer of theanine, L-Gln(Et)-OH, 2R enantiomer;and a DL-enantiomer of theanine, DL -Gln(Et)-OH enantiomer. The puritypercentages of the D-enantiomers of theanine, D-Glu(NHEt)-OH, 2 Renantiomer and D-Gln(Et)-OH, 2R enantiomer; the L enantiomers oftheanine, L-Glu(NHEt)-OH, 2 R enantiomer and L-Gln(Et)-OH, 2Renantiomer; and the DL-enantiomers of theanine, DL-Glu(NHEt)-OH, 2Renantiomer and DL-Gln(Et)-OH, 2R enantiomer in compositions according toembodiments of the present invention is 99+%; 99+% 2 R enantiomer. TheD-enantiomer at 99+%; 99+% ee % (2R) is where the first measure is theoverall chemical purity (hplc) and where the second measure is ee % (2R)known as the “percent enantiomeric excess.” The %ee is the measure ofchiral purity equal to [% R-% S/% R]*1 00 defined by the ratios of theirdiasteriomeric derivatives. Purity percentages may range from 90% to99.99% in any D or L configuration of any theanine or any enantiomerthereof.

Embodiments of the present invention may include cocrystal compositionsof acetylsalicylic acid and alpha variants of L-theanine,acetylsalicylic acid and alpha variants of D-theanine, andacetylsalicylic acid and alpha variants of DL-theanine.

Non-limiting examples of alpha variants used in embodiments according tothe present invention may include L-northeanine, D-northeanine,DL-northeanine, L-homotheanine, D-homotheanine, DL-homotheanineL-bishomotheanine, D-bishomotheanine, and DL-bishomotheanine, i.e., therespective C−1, C+1, and C+2 homologous analogues of theanine.

According to embodiments of the present invention the L-, D-, DL-alphaamino acids of theanine and their side-chain carbon homologues (nor,homo, and bishomologues) may have a functional R-group, where R1 maycontain linear, cyclic, or branched alkyl groups and derivativesthereof; linear, cyclic, or branched alkenyl groups and derivativesthereof; and aromatic radicals and derivatives thereof. In embodimentsof the present invention, the aromatic radicals may be aryl radicals.

According to the embodiments of the present invention the singleenantiomers (S and R) and racemic forms (S, R-mixture) of the beta aminoacids of theanine may have a functional R-group, where R1 may containlinear, cyclic, or branched alkyl groups and derivatives thereof;linear, cyclic, or branched alkenyl groups and derivatives thereof; andaromatic radicals and derivatives thereof. In embodiments of the presentinvention, the aromatic radicals may be aryl radicals.

Embodiments of the present invention may include cocrystal compositionsof acetylsalicylic acid and the enantiomers, L- and D-isomers, D,L-racemic mixture, S- and R-isomers, S, R-racemic mixtures, allrotamers, tautomers, salt forms, and hydrates of the alpha and betaamino acids of theanine in which the N-substituted functional R1-group[C4 or gamma-CH2—C(O)—NR1] may contain linear, cyclic, or branched alkylgroups and derivatives thereof; linear, cyclic, or branched alkenylgroups and derivatives thereof; and aromatic radicals and derivativesthereof making up all the analogue forms of theanine. In embodiments ofthe present invention, the aromatic radicals may be aryl radicals.

An aqueous solution is a solution in which water is the dissolvingmedium or solvent, and which is essentially free of colloidal solids.Dissolved crystals form true solutions and are capable of passingthrough a semi-permeable membrane as in dialysis, whereas colloids areunable to pass through a semi-permeable membrane. The compositionsaccording to embodiments of the present invention form a true solutionwhen dissolved in water, are able to pass through a semi-permeablemembrane, and can be used in dialysis. Examples of aqueous solutionsthat may be used in embodiments of the present invention include purewater, and the following: D5W, D10W, D50, D5 0.3% NS, D5 0.45% NS, 0.45%NS, D5 0.9% NS, 0.9% NS, 3% NaCl, D5RL, LR, NaHCO₃, and Xylitolsolutions.

Solutions formed by dissolving acetylsalicylic acid-theanine cocrystalcompositions according to embodiments of the present invention in waterdo not contain colloidal particles, and hence, do not exhibit the strongTyndall effect characteristic of colloidal dispersions.

It should be understood that the term “suitable,” as it is used herein,generally refers to the fact that the solution can be administeredintravenously to humans, without causing unfavorable side effects.

The effective amount of acetylsalicylic acid administered to a patient(i.e., the amount that will have a salutary effect with regards to adisease or condition being treated) will be influenced by gender, age,weight, body fluid status, severity of the disease or condition beingtreated, liver enzyme function, and renal excretion of salicylate which,in turn, is dependent upon urine pH, and protein binding of salicylates,which is concentration-dependent.

The term “carbohydrate,” as it is used herein, generally refers tosimple organic compounds that are aldehydes or ketones substituted withmultiple hydroxyl groups, of the general formula(CH₂O)_(n), where n isany number of three or greater.

Monosaccharides, disaccharides, trisaccharides, oligosaccharides,polysaccharides, dipeptides, and combinations of these may be used withthe acetylsalicylic acid—theanine cocrystal compositions according toembodiments of the present invention, in particular, with thosecocrystals formed according to the steps applied in Examples 1-8 below.

Compositions according to embodiments of the present invention maycontain the trisaccharide theanderose (G6-α-glucosyl sucrose), asubstance found specifically in honey.

Non-limiting examples of other natural sugars that may be used inembodiments of the present invention include abequose, allose, allulose,altrose, apiose, arabinose, beet oligosaccharides, bifurcose,deoxyribose, dextrose(D-glucose), erlose, erythrose, erythrulose,fructose (levulose), fucose, fuculose, galactose, gentiobiose,gentiotriose, gentiotetraose, etc., gulose, hamamelose, inulobiose,inulotriose, inulotetraose, isomaltose, isomaltotriose,isomaltotetraose, isomaltopentaose, isomaltulose (palatinose), kestose,kojibiose, lactose, lactulose, laminaribiose, lyxose, mannose, maltose,maltotriose, maltotetraose, etc., maltulose, meletzitose, melibiose,methose, nigerose, nystose, panose, paratose, primeverose, psicose,raffinose, rhamnose, ribose, ribulose, rutinose, sorbinose, sorbose,soybean oligosaccharides, stachyose, sucrose, tagatose, talose,theanderose, threose, trehalose, turanose, xylobiose, xylotriose, etc.,xylose, or xylulose, all of which may be used with acetylsalicylic acidin compositions according to embodiments of the present invention. Thecarbohydrates used in embodiments of the present invention may be oftheir respective D- or L-configurations.

In certain embodiments, non-limiting examples of sugar alcohols that maybe used include allitol, arabitol, erythritol, galactitol, glycerol,glycol, iditol, inositol, isomalt, lactitol, maltotetraol, maltotriol,mannitol, ribitol, sorbitol, talitol, threitol, and xylitol. The sugaralcohols used in embodiments according to the present invention may beof their respective the D- or L-configurations. These sugar alcoholshave the benefits of having low glycemic indices. Mannitol, for example,has been used to treat increased intracranial pressure. The followingcrystalloids may be used in formulations according to embodiments of thepresent invention: D5W, D10W, D50, D5 0.3% NS, D5 0.45% NS, 0.45% NS, D50.9% NS, 0.9% NS, 3% NaCl, D5RL, LR, NaHCO₃, and Xylitol solutions.

Formulations according to embodiments of the present invention may befully dissolved in an aqueous solution and administered via theparenteral route. The following infusion fluids may be used informulations according to embodiments of the present invention: D5W,D10W, D50, D5 0.3% NS, D5 0.45% NS, 0.45% NS, D5 0.9% NS, 0.9% NS, 3%NaCI, D5RL, LR, NaHCO₃, and Xylitol solutions.

Next, the present invention will be described in further detail by meansof examples, without intending to limit the scope of the presentinvention to these examples alone. The following are exemplaryformulations of water-soluble acetylsalicylic acid compositions inaccordance with the present invention.

EXAMPLE 1

A cocrystal product of the present invention was prepared by weighing352 mg of acetylsalicylic acid and 340 mg of L-theanine, andtransferring the solids to an agate mortar. The solids were wetted with500 μL of methanol, and hand-ground with a pestle until a driedcrystalline mass was obtained. This product was characterized usingdifferential scanning calorimetry (“DSC;” see FIG. 2), x-ray powderdiffraction (“XRPD;”see FIG. 3), Fourier-transform infrared spectroscopywith attenuated total reflectance sampling (“FTIR-ATR;” see FIG. 4), andRaman spectroscopy with diffuse reflectance sampling (“RAM-DR;” see FIG.5). In addition, 117 mg of the cocrystal product was found to dissolvein 13 mL of water, making the aqueous solubility approximately 9 mg/mL.

EXAMPLE 2

The aqueous solution formed in Example 1 was poured in an evaporatingdish, and allowed to dry completely. The DSC thermogram of the solidproduct is reflected in FIG. 2, the XRPD pattern is reflected in FIG. 3,the FTIR-ATR spectrum is reflected in FIG. 4, and the RAM-DR spectrum isreflected in FIG. 5.

EXAMPLE 3

1.721 g of acetylsalicylic acid and 1.667 g of L-theanine were weighedand transferred into a large glass mortar. The solids were wetted with20 mL of methanol, and hand-ground with a pestle until a driedcrystalline mass was obtained. The DSC thermogram of the solid productis reflected in FIG. 2, the XRPD pattern is reflected in FIG. 3, theFTIR-ATR spectrum is reflected in FIG. 4, and the RAM-DR spectrum isreflected in FIG. 5. 752 mg of the cocrystal product was found todissolve in 80 mL of water, making the aqueous solubility 9.4 mg/mL.

Aliquots of the aqueous solution were separately diluted in 1:1 v/vratios with (a) pH 7.4 tromethamine buffer, (b) 0.9% saline solution,(c) 7.5% sodium bicarbonate solution, (d) 5% dextrose for injection, and(e) 50% dextrose for injection. The solutions were observed to remainphysically unchanged over a six-day period, indicating compatibility ofthe cocrystal product with each of the infusion solutions.

EXAMPLE 4

435 mg of acetylsalicylic acid and 424 mg of L-theanine were weighedinto a 200 mL round-bottomed flask, and dissolved in 100 mL of water.The resulting clear solution was then dried using rotatory evaporationuntil a dried crystalline mass was obtained. The DSC thermogram of thissolid product is reflected in FIG. 2, the XRPD pattern is reflected inFIG. 3, the FTIR-ATR spectrum is reflected in FIG. 4, and the RAM-DRspectrum is reflected in FIG. 5. 752 mg of the cocrystal product wasfound to dissolve in 80 mL of water, making the aqueous solubility 9.4mg/mL.

EXAMPLE 5

A cocrystal product of the present invention was prepared by weighing353 mg of acetylsalicylic acid and 341 mg of D-theanine, andtransferring the solids to an agate mortar. The solids were wetted with500 μL of methanol, and hand ground with a pestle until a driedcrystalline mass was obtained. Representative photomicrographs of thecocrystal product are shown in FIG. 6 This product was characterizedusing differential scanning calorimetry (DSC; see FIG. 7), x-ray powderdiffraction (XRPD; see FIG. 8), Fourier-transform infrared spectroscopywith attenuated total reflectance sampling (FTIR-ATR; see FIG. 9), andRaman spectroscopy with diffuse reflectance sampling (RAM-DR; see FIG.10). In addition, 68 mg of the cocrystal product was found to dissolvein 7.5 mL of water, making the aqueous solubility approximately 9 mg/mL.

EXAMPLE 6

363 mg of acetylsalicylic acid and 354 mg of D-theanine were weighedinto a 150 mL beaker, and dissolved in 100 mL of water. The resultingclear solution was then dried using rotatory evaporation until a driedcrystalline mass was obtained. The DSC thermogram of this solid productis reflected in FIG. 7, the XRPD pattern is reflected in FIG. 8, theFTIR-ATR spectrum is reflected in FIG. 9, and the RAM-DR spectrum isreflected in FIG. 10.

EXAMPLE 7

A cocrystal product of the present invention was prepared by weighing368 mg of acetylsalicylic acid, 179 mg of L-theanine, and 178 mg ofD-theanine, and transferring the solids to an agate mortar. The solidswere wetted with 500 μL of methanol, and hand ground with a pestle untila dried crystalline mass was obtained. Representative photomicrographsof the cocrystal product are shown in FIG. 11. This product wascharacterized using differential scanning calorimetry (DSC; see FIG.12), x-ray powder diffraction (XRPD; see FIG. 13), Fourier-transforminfrared spectroscopy with attenuated total reflectance sampling(FTIR-ATR; see FIG. 14), and Raman spectroscopy with diffuse reflectancesampling (RAM-DR; see FIG. 15). In addition, 67 mg of the cocrystalproduct was found to dissolve in 9.5 mL of water, making the aqueoussolubility approximately 7 mg/mL.

EXAMPLE 8

358 mg of acetylsalicylic acid, 175 mg of L-theanine, and 174 mg ofD-theanine were weighed into a 150-mL beaker, and dissolved in 100 mL ofwater. The resulting clear solution was then dried using rotatoryevaporation until a dried crystalline mass was obtained. The DSCthermogram of this solid product is reflected in FIG. 12, the XRPDpattern is reflected in FIG. 13, the FTIR-ATR spectrum is reflected inFIG. 14, and the RAM-DR spectrum is reflected in FIG. 15.

The Tyndall effect is observed when particles of a solid are dispersedin water but not dissolved. Such an effect is strongly observed indispersions of Bayer aspirin, Disprin, and Aspro Clear. No such strongeffect is observed in water, or when cocrystal compositions according toembodiments of the present invention are dissolved in water. Colloidsare particles which range in size from 1-1000 nm, and a Tyndall effectis created when a laser beam is scattered by its passage through acolloidal dispersion of non-dissolved particles. For such dispersions,the illumination of a visible path through the colloidal dispersion isobservable. A true solution, such as water or a composition according toembodiments of the present invention dissolved in water, does notcontain colloidal particles, and hence does not exhibit a strong Tyndalleffect characteristic of colloidal dispersions. These findings, detailedbelow, as well as the preceding examples, demonstrate that compositionsaccording to embodiments of the present invention dissolve to form truesolutions in water, and do not merely disperse to form a colloidaldispersion.

TYNDALL EXPERIMENT 1 Comparison of Aspirin:(L)-Theanine CocrystalProduct with Disprin

300 mg of the aspirin:(L)-theanine cocrystal product was dissolved in150 ml of water in one beaker and a 325 mg tablet of Disprin wasdispersed in 150 ml of water in another beaker. A 514 nm laser beam wasfirst passed through the aspirin:(L)-theanine cocrystal solution andthen through the Disprin dispersion. A strong Tyndall effect wasobserved in the aqueous dispersion of Disprin, but was not observed withthe composition according to the present invention dissolved in water.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersions in the beakers were stirred to collect any undissolved solidin the center. An accumulation of undissolved solid formed at the bottomof the Disprin beaker, but not in the beaker containing aspirin(L)-theanine cocrystal product which displayed a crystal-clear solution.

TYNDALL EXPERIMENT 2 Comparison of Aspirin:(L)-Theanine CocrystalProduct with Aspro Clear

300 mg of the aspirin:(L)-theanine cocrystal product was dissolved in150 ml of water in one beaker and a 300 mg tablet of Aspro Clear wasdispersed in 150 ml water in another beaker. A 514 nm laser beam wasfirst passed through the aspirin :(L)-theanine cocrystal solution andthen through the Aspro Clear dispersion. A strong Tyndall effect wasobserved in the aqueous dispersion of Aspro Clear, but was not observedwith the composition according to the present invention dissolved inwater.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersions in the beakers were stirred to collect any undissolved solidin the center. An accumulation of undissolved solid formed at the bottomof the Aspro Clear beaker, but not in the beaker containing aspirin:(L)-theanine cocrystal product which exhibited a crystal-clearsolution.

TYNDALL EFFECT EXPERIMENT 3 Comparison of Aspirin:(L)-Theanine CocrystalProduct with Bayer Aspirin

300 mg of the aspirin:(L)-theanine cocrystal product was dissolved in150 ml of water in one beaker and a 325 mg tablet of Bayer aspirin wasdispersed in 150 ml of water in another beaker. A 514 nm laser beam wasfirst passed through the aspirin:(L)-theanine cocrystal solution andthen through the Bayer aspirin dispersion. A strong Tyndall effect wasobserved in the aqueous dispersion of Bayer aspirin, but was notobserved with the composition according to the present inventiondissolved in water.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersions in the beakers were stirred to collect any undissolved solidin the center. An accumulation of undissolved solid formed at the bottomof the Bayer aspirin beaker, but not in the beaker containingaspirin:(L)-theanine cocrystal product which displayed a crystal-clearsolution.

TYNDALL EFFECT EXPERIMENT 4 Comparison of Aspirin:(L)-Theanine CocrystalProduct with Water

300 mg of the aspirin:(L)-theanine cocrystal product was dissolved in150 ml of water in one beaker and 150 ml of water alone was place inanother beaker. A 514 nm laser beam was first passed through theaspirin: (L)-theanine cocrystal solution and then through the water. Astrong Tyndall effect was not observed with water, nor was it observedwith the composition according to the present invention dissolved inwater. Both water and the aspirin:(L)-theanine cocrystal productexhibited crystal-clear solutions and were indistinguishable from oneother.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersion in the beaker containing the dissolved aspirin:(L)-theaninecocrystal product was stirred to collect any undissolved solid in thecenter. No undissolved solids were observed at the bottom of the beakerwith the aspirin:(L)-theanine cocrystal product. Both water and theaspirin :(L)-theanine cocrystal product produced crystal-clear solutionsand were indistinguishable from one other.

TYNDALL EFFECT EXPERIMENT 5 Comparison of Aspirin:(D)-Theanine CocrystalProduct with Dispirin

300 mg of the aspirin:(D)-theanine cocrystal product was dissolved in150 ml of water in one beaker and a 325 mg tablet of Disprin wasdispersed in 150 ml of water in another beaker. A 514 nm laser beam wasfirst passed through the aspirin:(D)-theanine cocrystal solution andthen through the Disprin dispersion. A strong Tyndall effect wasobserved in the aqueous dispersion of Disprin, but was not observed withthe composition according to the present invention dissolved in water.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersions in the beakers were stirred to collect any undissolved solidin the center. An accumulation of undissolved solid formed at the bottomof the Disprin beaker, but not in the beaker containing aspirin(D)-theanine cocrystal product which displayed a crystal-clear solution.

TYNDALL EFFECT EXPERIMENT 6 Comparison of Aspirin:(D)-Theanine CocrystalProduct with Aspro Clear

300 mg of the aspirin:(D)-theanine cocrystal product was dissolved in150 ml of water in one beaker and a 300 mg tablet of Aspro Clear wasdispersed in 150 ml water in another beaker. A 514 nm laser beam wasfirst passed through the aspirin :(D)-theanine cocrystal solution andthen through the Aspro Clear dispersion. A strong Tyndall effect wasobserved in the aqueous dispersion of Aspro Clear, but was not observedwith the composition according to the present invention dissolved inwater.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersions in the beakers were stirred to collect any undissolved solidin the center. An accumulation of undissolved solid formed at the bottomof the Aspro Clear beaker, but not in the beaker containingaspirin:(D)-theanine cocrystal product which displayed a crystal-clearsolution.

TYNDALL EFFECT EXPERIMENT 7 Comparison of Aspirin:(D)-Theanine CocrystalProduct with Bayer Aspirin

300 mg of the aspirin:(D)-theanine cocrystal product was dissolved in150 ml of water in one beaker and a 325 mg tablet of Bayer aspirin wasdispersed in 150 ml of water in another beaker. A 514 nm laser beam wasfirst passed through the aspirin:(D)-theanine cocrystal solution andthen through the Bayer aspirin dispersion. A strong Tyndall effect wasobserved in the aqueous dispersion of Bayer aspirin, but was notobserved with the composition according to the present inventiondissolved in water.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersions in the beakers were stirred to collect any undissolved solidin the center. An accumulation of undissolved solid formed at the bottomof the Bayer aspirin beaker, but not in the beaker containing aspirin(D)-theanine cocrystal product which displayed a crystal-clear solution.

TYNDALL EFFECT EXPERIMENT 8 Comparison of Aspirin:(D)-Theanine CocrystalProduct with Water

300 mg of the aspirin:(D)-theanine cocrystal product was dissolved in150 ml of water in one beaker and 150 ml of water alone was placed inanother beaker. A 514 nm laser beam was first passed through theaspirin:(D)-theanine cocrystal solution and then through the water. Astrong Tyndall effect was not observed with water, nor was it observedwith the composition according to the present invention dissolved inwater. Both water and the aspirin:(D)-theanine cocrystal productproduced crystal-clear solutions and were indistinguishable from oneother.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersion in the beaker containing the dissolved aspirin: (D)-theaninecocrystal product was stirred to collect any undissolved solid in thecenter. No undissolved solids were observed at the bottom of the beakerwith the aspirin:(D)-theanine cocrystal product. Both water and theaspirin:(D)theanine cocrystal product produced crystal-clear solutionsand were indistinguishable from one other.

TYNDALL EFFECT EXPERIMENT 9 Comparison of Aspirin:(DL)-TheanineCocrystal Product with Dispirin

300 mg of the aspirin:(DL)-theanine cocrystal product was dissolved in150 ml of water in one beaker and a 325 mg tablet of Disprin wasdispersed in 150 ml of water in another beaker. A 514 nm laser beam wasfirst passed through the aspirin:(DL)-theanine cocrystal solution andthen through the Disprin dispersion. A strong Tyndall effect wasobserved in the aqueous dispersion of Disprin, but was not observed withthe composition according to the present invention dissolved in water.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersions in the beakers were stirred to collect any undissolved solidin the center. An accumulation of undissolved solid formed at the bottomof the Disprin beaker, but not in the beaker containingaspirin:(DL)-theanine cocrystal product which displayed a crystal-clearsolution.

TYNDALL EFFECT EXPERIMENT 10 Comparison of Aspirin:(DL)-TheanineCocrystal Product with Aspro Clear

300 mg of the aspirin:(DL)-theanine cocrystal product was dissolved in150 ml of water in one beaker and a 300 mg tablet of Aspro Clear wasdispersed in 150 ml water in another beaker. A 514 nm laser beam wasfirst passed through the aspirin:(DL)-theanine cocrystal solution andthen through the Aspro Clear dispersion. A strong Tyndall effect wasobserved in the aqueous dispersion of Aspro Clear, but was not observedwith the composition according to the present invention dissolved inwater.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersions in the beakers were stirred to collect any undissolved solidin the center. An accumulation of undissolved solid formed at the bottomof the Aspro Clear beaker, but not in the beaker containing aspirin(DL)-theanine cocrystal product which displayed a crystal-clearsolution.

TYNDALL EFFECT EXPERIMENT 11 Comparison of Aspirin:(DL)-TheanineCocrystal Product with Bayer Aspirin

300 mg of the aspirin:(DL)-theanine cocrystal product was dissolved in150 ml of water in one beaker and a 325 mg tablet of Bayer aspirin wasdispersed in 150 ml of water in another beaker. A 514 nm laser beam wasfirst passed through the aspirin:(DL)-theanine cocrystal solution andthen through the Bayer aspirin dispersion. A strong Tyndall effect wasobserved in the aqueous dispersion of Bayer aspirin, but was notobserved with the composition according to the present inventiondissolved in water.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersions in the beakers were stirred to collect any undissolved solidin the center. An accumulation of undissolved solid formed at the bottomof the Bayer aspirin beaker, but not in the beaker containing aspirin(DL)-theanine cocrystal product which displayed a crystal-clearsolution.

TYNDALL EFFECT EXPERIMENT 12 Comparison of Aspirin:(DL)-TheanineCocrystal Product with Water

300 mg of the aspirin:(DL)-theanine cocrystal product was dissolved in150 ml of water in one beaker and 150 ml of water alone was placed inanother beaker. A 514 nm laser beam was first passed through theaspirin:(DL)-theanine cocrystal solution and then through the water. Astrong Tyndall effect was not observed with water, nor was it observedwith the composition according to the present invention dissolved inwater. Both water and the aspirin:(DL)-theanine cocrystal productproduced crystal-clear solutions and were indistinguishable from oneother.

An investigation regarding the degree of insoluble substance remainingafter performance of the Tyndall effect experiment was carried out. Thedispersion in the beaker containing the dissolved aspirin:(DL)-theaninecocrystal product was stirred to collect any undissolved solid in thecenter. No undissolved solids were observed at the bottom of the beakerwith the aspirin :(DL)-theanine cocrystal product. Both water and theaspirin:(DL)-theanine cocrystal product produced crystal-clear solutionsand were indistinguishable from one other.

Derivatives prepared using compositions according to embodiments of thepresent invention can be administered via intravenous, intramuscular,intradermal, subcutaneous, intraperitoneal, intraarticular, sublingual,subconjunctival, and intravitreal routes, or in the form of eye drops,orally, topically, rectally, via nasal spray, inhalation, andnanoparticle delivery systems.

The pharmaceutical compositions according to embodiments of the presentinvention may be prepared as oral solids (tablets, oral disintegratingtablets, effervescent tablets, capsules),oral liquids, hard or softgelatin capsules,quick dissolve, controlled released, modified released,syrups, suspensions, granules, wafers (films), pellets, lozenges,powders, chewables, suppositories, ointments, solutions,parenteral/injectable powders or granules that are pre-mixed orreconstituted, lotions, gels, creams, foams, and nanoemulsions.

The pharmaceutical compositions according to embodiments of the presentinvention may be combined with lipooxygenase inhibitor agents, naturallipooxygenase inhibitors, anti-hypertensive agents, anti-hyperlipidemicagents, anti-hypertensive/anti-hyperlipidemic agents, anti-triglycerideagents, anti-migraine agents, blood modifier agents, especiallythrombolytic agents and platelet aggregation inhibitor agents,anti-neoplastic agents, anti-psychotic agents, anti-anxiety agents,anti-convulsant agents, anti-Parkinsonian agents, anti-diabetic agents,anti-inflammatory agents such as corticosteroids, anti-pyretic agentsexcluding NSAIDS (NSAIDS when combined with aspirin, negate the effectsof aspirin), anti-rheumatic agents excluding NSAIDS, agents fortreatment of symptoms associated with premenstrual syndrome excludingNSAIDS, anti-arrhythmic agents, digitalis glycosides, anti-anginalagents (nitrates, anti-platelet agents, beta blockers, calcium channelblockers and ranolazine), analgesic agents, musculoskeletal relaxants,anti-infective agents especially antibiotics, parenteral nutritionalagents, magnesium, Co-enzyme Q₁₀, sarcosine, amino acids, vitamins(except vitamin K), and agents used to treat diseases associated withexcess amounts of glutamate such as, but not limited to amyotrophiclateral sclerosis, cerebrovascular dementia, and with brain injuries, asoccurs with non-hemorrhagic strokes or physical injuries. Thepharmaceutical compositions of the invention with theanine are notlimited to these agents.

Intravenous formulations according to embodiments of the presentinvention include new compounds that are combinedlipooxygenase/cyclooxygenase inhibitors for treatment of, among otherthings, myocardial ischemia, myocardial infarction, cerebral ischemia,stroke, atherosclerosis, retinal ischemia, rheumatoid arthritis,osteoarthritis, inflammatory bowel disease, and certain types ofcancers.

Embodiments of the present invention have other potential clinicalapplications including, but not limited to the following: cardiovascular(treatment of acute coronary syndrome, treatment of acute myocardialinfarction, adjunctive therapy in revascularization procedures:percutaneous transluminal coronary angioplasty, coronary artery bypassgrafts, carotid enarterectomy, and stent implantation); neurologic(treatment of acute ischemic stroke); dysphagia (from any etiology);rheumatologic (rheumatoid arthritis, ankylosing spondylitis,spondyloarthropathies, pleurisy and arthritis of systemic lupuserythematous, psoriatic arthritis, fibromyalgia, Reiter's syndrome,osteoarthritis, Lyme arthritis and gonorrhea arthritis);anti-inflammatory (epididymitis, Bornholm's disease (coxsackiemyocarditis), acute pericarditis, Dressler's syndrome, acute rheumaticfever, Ross River fever); pain management (marine envenomations such asfrom jellyfish, sea urchins, star fish, Portuguese man-of-wars, firecorals, sea anemones, lionfish, stonefish, and stingrays;Osgood-Schlatterdisease, idiopathic (primary) erythromelalgia, burns,acute renal colic, trigeminal neuralgia, bone pain (osteoid osteomas,Pagets disease, sickle cell anemia), spinal stenosis, metastaticdisease, intractable headaches, radiculopathies, and other chronic painsyndromes; as an adjuvant to morphine for patient-controlled analgesia(PCA); ophthalmologic (retinal ischemia and retinal occlusion); emergentuse (in ambulances, hospital emergency rooms and critical care units,doctors' offices, air travel, in the wilderness, etc.); with intubatedpatients and patients with severely compromised bowel function,excluding Crohn's disease and ulcerative colitis; as an anti-pyretic forhigh grade temperatures, excluding malignant hyperthermia; forprevention of post-anesthetic shivering; for closure of patent ductusarteriosus; for familial cylindromatosis; for inhibition ofangiogenesis; for inhibition of niacin flushing; as an adjuvant tothrombolytic therapy for the treatment of frostbite; the treatment ofrare diseases (including Kawasaki disease, Riedel thyroiditis,adult-onset Still's disease, Kikuchi-Fujimoto disease, focal myositis,Weber-Christian disease, and adhesive arachnoiditis); substantialprotection against hepatotoxic effects from drugs, alcohol, herbs,toxins, chemicals, obesity-related liver disease and radiation-inducedliver disease; and for providing anti-HIV effects.

Embodiments of the present invention may be employed to providesubstantial protection against a wide variety of medical conditions,including but not limited to, the hepatotoxic effects from Tylenol,statins, antiretrovirals, alcohol, and other drugs, toxins, herbs, andchemicals that are capable of inducing hepatoxicity; obesity-relatedliver disease; and radiation-induced liver disease.

Cocrystals according to embodiments of the present invention may be usedto improve one or more physical properties, such as solubility,stability, and dissolution rate, of the active pharmaceutical ingredientof a selected treatment or prevention.

While specific embodiments of the invention have been shown anddescribed in detail to illustrate the application of the principles ofthe invention, it will be understood that the invention may be embodiedotherwise without departing from such principles.

1. A method of making a parenteral fluid, comprising the steps of:providing a quantity of acetylsalicylic acid; adding a quantity ofL-theanine to said quantity of acetylsalicylic acid to form a mixturecomprising said quantity of acetylsalicylic acid and said quantity ofL-theanine; dissolving said mixture in a quantity of a first solvent toform a solution; drying said solution for a length of time sufficient toproduce a dried crystalline mass of an acetylsalicylic acid-theaninecocrystal composition; dissolving said dried crystalline mass in asecond solvent to form an acetylsalicylic acid -theanine cocrystalsolution; and adding said acetylsalicylic acid-theanine cocrystalsolution to an infusion fluid.
 2. The method of claim 1, wherein theinfusion fluid is selected from the group consisting of D5W, D10W, D50,D5 0.3% NS, D5 0.45% NS, 0.45% NS, D5 0.9% NS, 0.9% NS, 3% NaCl, D5RL,LR, and NaHCO₃.
 3. The method of claim 1, wherein said dried crystallinemass has an aqueous solubility of at least about 9.4 mg/mL.
 4. Themethod of claim 1, further comprising adding a sugar alcohol to saidsolution.
 5. The method of claim 4, wherein said sugar alcohol has anL-configuration.
 6. The method of claim 1, wherein said first solvent iswater.
 7. The method of claim 1, wherein said second solvent is water.8. The method of claim 1, wherein the pH of said acetylsalicylicacid-theanine cocrystal solution is physiologic.